ABSTRACT
Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.
Subject(s)
Humans , Anthraquinones , Chemistry , Pharmacology , Antineoplastic Agents , Chemistry , Pharmacology , Aziridines , Chemistry , Pharmacology , Cell Hypoxia , Indolequinones , Chemistry , Pharmacology , Molecular Structure , NAD(P)H Dehydrogenase (Quinone) , Chemistry , Pharmacology , Neoplasms , Drug Therapy , Pathology , Nitrogen Mustard Compounds , Chemistry , Pharmacology , Nitroimidazoles , Chemistry , Pharmacology , Phosphoramide Mustards , Chemistry , Pharmacology , Prodrugs , Chemistry , Pharmacology , Triazines , Chemistry , PharmacologyABSTRACT
Oxazaphosphorines belong to a group of alkylating agents. Mafosfamide cyclohexylamine salt (D-17272), 4-hydro-peroxy-cyclophosphamide (D-18864) and glufosfamide (D-19575, β-D-glucose-isophosphoramide mustard) are new generation oxazaphosphorines. The objective of the present study was to compare the cytotoxic action of these oxazaphosphorine compounds against human histiocytic lymphoma U937 cells. The chemical structures of the oxazaphosphorines were responsible for the different responses of U937 cells. The cytotoxic effects of D-17272, D-18864, and D-19575 on U937 cells depended on the agent tested, its dose, and the time intervals after the oxazaphosphorine application. Among the oxazaphosphorine agents, D-18864 appeared to be the most cytotoxic, and D-19575 was characterized by the lowest cytotoxicity. The in vitro cytotoxic activities of the oxazaphosphorines were strongly associated with their cell death inducing potential.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Cyclophosphamide/analogs & derivatives , Cyclophosphamide/pharmacology , Flow Cytometry , Glucose/analogs & derivatives , Glucose/pharmacology , Humans , Ifosfamide/analogs & derivatives , Ifosfamide/pharmacology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Membrane Potential, Mitochondrial/drug effects , Necrosis , Phosphoramide Mustards/pharmacology , Tumor Cells, CulturedABSTRACT
<p><b>OBJECTIVE</b>To investigate the effect of lentivirus-mediated Bcl-2 gene transfection in protecting human primary ovarian granulosa cells against phosphoramide mustard (PM)-induced apoptosis.</p><p><b>METHODS</b>Granulosa cells were isolated from the follicle fluid of women undergoing in vitro fertilization and embryo transfer. The lentiviral vectors carrying Bcl-2 gene (pGC-FU-Bcl-2) and enhanced green fluorescence protein (pGC-FU-EGFP) were constructed and packaged into high-titer lentiviruses. The resulting recombinant lentivirus carrying Bcl-2 and EGFP genes or the empty vector were used to infect the primary human ovarian granulosa cells, followed by addition of PM in the cell culture, with untreated granulosa cells as the control. The cell apoptosis was detected by Annexin V and Hochst 33258 staining, and the expression of Bcl-2 protein was assessed using Western blotting.</p><p><b>RESULTS</b>The control granulosa cells showed an apoptotic rate of (1.93±0.28)%. The cells infected with pGC-FU-Bcl-2 prior to PM exposure had a apoptotic rate of (6.99±10.55)%, significantly higher than that of the control cells, but significantly lower than that of the cells with PM exposure only and those infected with the empty vector before PM exposure (P<0.05). The expression of Bcl-2 was the highest in the cells infected with pGC-FU-Bcl-2 prior to PM exposure (P<0.05).</p><p><b>CONCLUSION</b>Lentivirus-mediated Bcl-2 gene transfection can protect human ovarian granulosa cells against PM-induced apoptosis by upregulating Bcl-2 protein expression.</p>
Subject(s)
Adult , Female , Humans , Apoptosis , Genes, bcl-2 , Genetic Vectors , Granulosa Cells , Lentivirus , Genetics , Phosphoramide Mustards , TransfectionABSTRACT
<p><b>AIM</b>To elucidate the metabolic pathway of glufosfamide in rats.</p><p><b>METHODS</b>In this study, a liquid chromatography-tandem mass spectrometric method was developed and applied to characterize the metabolites of glufosfamide in rat urine, after an i.v. administration of 50 mg x kg(-1). The analysis was performed under two ionization modes in two different chromatographic systems, separately. To make sure that the compounds detected in rat urine were metabolites or degradation products, the stability of glufosfamide, isophosphoramide mustard (M1), and the degradation products of M1 in urine were investigated.</p><p><b>RESULTS</b>In positive ionization mode, besides glufosfamide, two metabolites, isophosphoramide mustard and monoaziridinyl derivative of isophosphoramide mustard, were detected. In negative ionization mode, only glufosfamide itself was detected, while derivatives of isophosphoramide mustard have no response in such condition.</p><p><b>CONCLUSION</b>Glufosfamide was mainly unchanged excreted in urine, and two metabolites were detected as isophosphoramide mustard and monoaziridinyl derivative of isophosphoramide mustard.</p>